Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

NCT01670877 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 201209135
• Study Type: interventional
• Target: 56
• Locations: 2 countries
• Sites: 17

Brief Summary

This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.

Conditions

Breast Neoplasms

Keywords

Neratinib; fulvestrant; HER2 mutation; metastatic breast cancer; trastuzumab

Outcome Measures

Primary Outcomes (4)

• Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone

  * Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

  Through completion of treatment (median treatment time of 90 days, full range 54-716 days)

• Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation

  * Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

  Through completion of treatment (median treatment time of 62 days, full range 56-413 days)

• Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation

  * Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

  Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)

• Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation

  * Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

  Through completion of treatment (median treatment time of 168 days, full range 28-671 days)

Secondary Outcomes (11)

• Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)

  Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 92 days, full range 86 days-443 days)

• Number of Participants With HER2 Mutation Subtype and Histology Subtype

  At the time of enrollment

• Number of Participants With HER2 Mutation Subtype and Tumor Grade

  A time of enrollment

• Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis

  At time of enrollment

• Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival

  Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 142 days, full range 54-800 days)

Study Arms (6)

Part I: Neratinib Only

EXPERIMENTAL

-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Drug: Neratinib; Procedure: Tumor biopsy; Procedure: Research blood sample

Part II: Neratinib Only (ER-)

EXPERIMENTAL

-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Drug: Neratinib; Procedure: Tumor biopsy; Procedure: Research blood sample

Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)

EXPERIMENTAL

-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Drug: Neratinib; Drug: Fulvestrant; Procedure: Tumor biopsy; Procedure: Research blood sample

Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)

EXPERIMENTAL

-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Drug: Neratinib; Drug: Fulvestrant; Procedure: Tumor biopsy; Procedure: Research blood sample

Crossover: Neratinib + Trastuzumab

EXPERIMENTAL

-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.

Drug: Neratinib; Drug: Trastuzumab; Procedure: Tumor biopsy; Procedure: Research blood sample

Crossover: Neratinib + Fulvestrant + Trastuzumab

EXPERIMENTAL

-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.

Drug: Neratinib; Drug: Fulvestrant; Drug: Trastuzumab; Procedure: Tumor biopsy; Procedure: Research blood sample

Interventions

Neratinib DRUG

Also known as: PF-05208767

Crossover: Neratinib + Fulvestrant + Trastuzumab; Crossover: Neratinib + Trastuzumab; Part I: Neratinib Only; Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive); Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx); Part II: Neratinib Only (ER-)

Fulvestrant DRUG

Also known as: Faslodex

Crossover: Neratinib + Fulvestrant + Trastuzumab; Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive); Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)

Trastuzumab DRUG

Also known as: Herceptin

Crossover: Neratinib + Fulvestrant + Trastuzumab; Crossover: Neratinib + Trastuzumab

Tumor biopsy PROCEDURE

-Optional at baseline and disease progression

Crossover: Neratinib + Fulvestrant + Trastuzumab; Crossover: Neratinib + Trastuzumab; Part I: Neratinib Only; Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive); Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx); Part II: Neratinib Only (ER-)

Research blood sample PROCEDURE

-Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)

Crossover: Neratinib + Fulvestrant + Trastuzumab; Crossover: Neratinib + Trastuzumab; Part I: Neratinib Only; Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive); Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx); Part II: Neratinib Only (ER-)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-amplified by FISH) breast cancer that is stage IV.
• Agree to provide archival tumor material for research
• There is no limitation on the number of prior lines of systemic therapy.
• Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except to be eligible for the Part II fulvestrant-naive ER+ cohort, at least one measurable disease by RECIST 1.1 is required.
• At least 18 years of age.
• ECOG performance status ≤ 2
• Adequate organ function as defined below within 8 weeks of pre-registration:
• Serum creatinine ≤1.5 x ULN
• Chil-Pugh class A if with liver disease
• Able to understand and willing to sign an IRB approved written informed consent document.
• Note: HER2 mutation testing may be performed while the patient is receiving active systemic therapy for metastatic breast cancer so that the result can be used to determine eligibility for study drug therapy in the future.

You may not qualify if:

• Testing for LVEF is not required for pre-registration, but patient must not have a recent LVEF \< LLN or have symptoms of congestive heart failure.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment).
• History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.
• Tumor tissue tested positive for HER2 mutation. HER2 mutations detected by Guardant360 are also eligible.
• Agree to provide archival tumor material for research
• ECOG performance status ≤2
• Adequate organ function as defined below within 2 weeks of registration:
• ANC ≥1.5 x 10\^9/L
• Platelet count ≥100 x 10\^9/L
• Serum creatinine ≤1.5 x ULN
• Child-Pugh class A if with liver disease
• The patient must have completed radiation therapy and be at least 1 week from the last systemic chemotherapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib.
• Presence of disease progression on the most recent disease evaluation.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Puma Biotechnology, Inc.: collaborator
• United States Department of Defense: collaborator

Study Sites (17)

University of Alabama Cancer Center

Birmingham, Alabama, 35294, United States

Location

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

University of Southern California Keck School of Medicine

Los Angeles, California, 90033, United States

Location

Stanford Medicine Cancer Institute

Stanford, California, 94305, United States

Location

University of Miami Hospital and Clinics

Miami, Florida, 33136, United States

Location

Northwestern University - Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Dana-Farber Cancer Institute, Harvard University

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

St. Luke's Cancer Institute

Kansas City, Missouri, 64111, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center)

Chapel Hill, North Carolina, 27514, United States

Location

Duke Cancer Institute at Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

BC Cancer Agency

Vancouver, British Columbia, V5Z 1L3, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (3)

• Jhaveri K, Eli LD, Wildiers H, Hurvitz SA, Guerrero-Zotano A, Unni N, Brufsky A, Park H, Waisman J, Yang ES, Spanggaard I, Reid S, Burkard ME, Vinayak S, Prat A, Arnedos M, Bidard FC, Loi S, Crown J, Bhave M, Piha-Paul SA, Suga JM, Chia S, Saura C, Garcia-Saenz JA, Gambardella V, de Miguel MJ, Gal-Yam EN, Rapael A, Stemmer SM, Ma C, Hanker AB, Ye D, Goldman JW, Bose R, Peterson L, Bell JSK, Frazier A, DiPrimeo D, Wong A, Arteaga CL, Solit DB. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol. 2023 Oct;34(10):885-898. doi: 10.1016/j.annonc.2023.08.003. Epub 2023 Aug 18.

  PMID: 37597578 DERIVED

• Shishido SN, Masson R, Xu L, Welter L, Prabakar RK, D' Souza A, Spicer D, Kang I, Jayachandran P, Hicks J, Lu J, Kuhn P. Disease characterization in liquid biopsy from HER2-mutated, non-amplified metastatic breast cancer patients treated with neratinib. NPJ Breast Cancer. 2022 Feb 18;8(1):22. doi: 10.1038/s41523-022-00390-5.

  PMID: 35181666 DERIVED

• Exman P, Garrido-Castro AC, Hughes ME, Freedman RA, Li T, Trippa L, Bychkovsky BL, Barroso-Sousa R, Di Lascio S, Mackichan C, Lloyd MR, Krevalin M, Cerami E, Merrill MS, Santiago R, Crowley L, Kuhnly N, Files J, Lindeman NI, MacConaill LE, Kumari P, Tolaney SM, Krop IE, Bose R, Johnson BE, Ma CX, Dillon DA, Winer EP, Wagle N, Lin NU. Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials. JCO Precis Oncol. 2019 Nov 15;3:PO.19.00087. doi: 10.1200/PO.19.00087. eCollection 2019.

  PMID: 32923853 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Breast Neoplasms

Interventions

neratinib; Fulvestrant; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Cynthia Ma, M.D., Ph.D.
• Organization: Washington University School of Medicine

cynthiaxma@wustl.edu

314-362-9383

Study Officials

• Cynthia Ma, M.D., Ph.D

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2012
• First Posted: August 22, 2012
• Study Start: December 11, 2012
• Primary Completion: February 11, 2021
• Study Completion: March 11, 2021
• Last Updated: April 15, 2022
• Results First Posted: April 15, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (15); CA (2)